Abstract

Monoacylglycerol lipase (MGL) is a ubiquitously expressed enzyme that catalyzes the hydrolysis of monoacylglycerols (MGs) to yield FFAs and glycerol. MGL contributes to energy homeostasis through the mobilization of fat stores and also via the degradation of the endocannabinoid 2-arachidonoyl glycerol. To further examine the role of MG metabolism in energy homeostasis, MGL(-/-) mice were fed either a 10% (kilocalories) low-fat diet (LFD) or a 45% (kilocalories) high-fat diet (HFD) for 12 weeks. Profound increases of MG species in the MGL(-/-) mice compared with WT control mice were found. Weight gain over the 12 weeks was blunted in both diet groups. MGL(-/-) mice were leaner than WT mice at both baseline and after 12 weeks of LFD feeding. Circulating lipids were decreased in HFD-fed MGL(-/-) mice, as were the levels of several plasma peptides involved in glucose homeostasis and energy balance. Interestingly, MGL(-/-) mice had markedly reduced intestinal TG secretion following an oral fat challenge, suggesting delayed lipid absorption. Overall, the results indicate that global MGL deletion leads to systemic changes that produce a leaner phenotype and an improved serum metabolic profile.

Tissue content of MG species as determined by LC/MS analysis in brain (A), liver (B), gonadal fat (C), and small intestine mucosa (D). Data are expressed as average ± SEM (n = 6). *P < 0.05 compared with control group of the same diet.

Tissue content of acylethanolamide (EA) species as determined by LC/MS analysis in brain (A), liver (B), gonadal fat (C), and small intestine mucosa (D). Data are expressed as average ± SEM (n = 6). *P < 0.05 compared with control group of the same diet.

Body composition and tissue weights in MGL−/− mice. A: Fat mass percentage for male and female mice at the beginning (baseline) and after 10 weeks of diet. B: Lean body mass at the beginning (baseline) and end of study. Gonadal (C) and retroperitoneal (perirenal) (D) fat pad weights at necropsy. Data are expressed as average ± SEM (n = 6). *P < 0.05 compared with control group of the same diet.

Plasma lipids in 12 h fasted mice after 12 weeks of LFD or HFD feeding. TG (A); Total cholesterol (B), and NEFA (C). Data from each male and female group were normalized to WT LFD and then both sexes combined. Data are expressed as average ± SEM (n = 11–12). *P < 0.05, **P < 0.01 compared with control group of the same diet.

Tissue gene expression measured by RT-PCR and analyzed by the ddCT method in brain (A), liver (B), and small intestine mucosa (C). All transcript levels are presented relative to the WT LFD group. Data are expressed as average ± SEM (n = 5–6). *P < 0.05, **P < 0.001 compared with control group of the same diet.